Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
2002-02-06
2002-10-22
Ford, John M. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
active
06469168
ABSTRACT:
The invention refers to novel piperazinylalkylthiopyrimidine derivatives, pharmaceutical compositions containing the same, and a process for the preparation of the active substance. The novel compounds can be employed mainly for the treatment of diseases that form due to disorders of the central nervous system.
More specifically, the invention refers to a novel piperazinylalkylthiopyrimidine derivative of the formula
wherein
R
1
represents a hydrogen atom, a C
1-4
alkyl group, a C
1-4
alkanoyl group or a di(C
1-4
alkyl)amino(C
1-4
alkyl) group,
R
2
stands for a hydrogen atom or a benzyl group substituted by 1 to 3 substituent(s) selected from the group consisting of a C
1-4
alkyl group, a C
1-4
alkoxy group, a di(C
1-4
alkyl)amino group, a hydroxy group and a halo atom,
n has a value of 2, 3 or 4,
and a pharmaceutically suitable acid addition salt thereof.
From Patent Application WO 97/16429, piperazinylalkylthiopyrimidine derivatives are known wherein the piperazine ring is substituted by a phenyl or a benzyl group at the nitrogen atom in position 4. The known compounds are suitable especially for the treatment of diseases of the central nervous system and have, for example, an outstanding anxiolytic activity. It is an important feature of the known compounds that they exert an effect at the serotonin receptors (5-HT
2A
, 5-HT
2C
). A considerable drawback of the known compounds resides in the fact that the compounds having the best anxiolytic effect metabolize very quickly in the living organism. Thus, the known compounds have a low biological utility that inhibits the development of drugs used in the clinical practice.
The aim of the invention is to prepare novel compounds that are effective mainly within the above field of biological action and more stable than the known compounds from the point of view of metabolism.
It was found that the above aim is achieved by the novel piperazinylalkylthiopyrimidine derivatives of the formula I having anxiolytic activity. However, the novel compounds do not exert any action on the serotonin receptors, and the metabolism thereof is not fast.
In the description, a C
1-4
alkyl group is a methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, tert.-butyl or isobutyl group. Preferably, a C
1-4
alkyl group is a methyl group or an isopropyl group.
A C
1-4
alkoxy group is, primarily, a methoxy, ethoxy, n-propoxy or n-butoxy group, preferably a methoxy group.
A halo atom is, in general, a fluoro, chloro or bromo atom, preferably a chloro atom or a fluoro atom.
Under a C
1-4
alkanoyl group a formyl, acetyl, n-propanoyl, n-butanoyl group etc., preferably an acetyl group is meant.
The pharmaceutically suitable acid addition salts of the compounds of the formula I are the acid addition salts of the compounds formed with pharmaceutically suitable inorganic or organic acids including sulfonic acids. Preferred acid addition salts are the hydrogen halides such as hydrochlorides or hydrobromides, carbonates, hydrogen carbonates, sulfates, phosphates, acetates, fumarates, maleates, citrates, ascorbates and benzenesulfonates.
A preferred subgroup of the compounds of the invention consists of the compounds of the formula I and the pharmaceutically suitable acid addition salts thereof, wherein
R
1
represents a hydrogen atom, a dimethylamino(C
1-4
alkyl) group or a C
1-4
alkanoyl group,
R
2
is as defined in connection with formula I,
n has a value of 2 or 3.
The especially preferred piperazinylalkylthiopyrimidine derivatives of the invention consist of the compounds of the formula I, wherein
R
1
represents a hydrogen atom or a dimethylamino(C
1-4
alkyl) group,
R
2
stands for a benzyl group substituted by a C
1-4
alkoxy group, or a fluoro atom,
n has a value of 2,
and pharmaceutically suitable acid addition salts thereof.
In the definition of R
2
, conveniently, the C
1-4
alkoxy group is in position ortho.
The compounds of the invention are prepared by reacting a 2-mercaptopyrimidine of the formula
wherein R
2
is as defined above, or an alkali metal salt thereof, with a haloalkylpiperazine of the formula
wherein R
1
and n are as stated above, HIg represents a halo atom, preferably a chloro or bromo atom, or an acid addition salt thereof, and, if desired, converting the compound of the formula I to a pharmaceutically suitable acid addition salt thereof, or liberating it from the acid addition salt thereof.
If desired, an obtained compound of the formula I can be transformed into another compound of the formula I. These additional transformations can be performed in a manner known per se. Thus, an obtained compound of the formula I, wherein R
1
is a hydrogen atom, can be alkylated to obtain a compound of the formula I, wherein R
1
stands for a C
1-4
alkyl group. Compounds of the formula I, wherein R
1
represents a dialkylaminoethyl group or an alkanoyl group, can be prepared through a similar additional transformation (alkylation or acylation). According to a further example of the additional transformation, a compound of the formula I, wherein R
2
stands for an alkoxybenzyl group, is prepared by alkylating a compound of the formula I, wherein R
2
is a hydroxybenzyl group, or a compound of the formula I, wherein R
1
is a hydrogen atom, is prepared from the corresponding compound of the formula I, wherein R
1
is a formyl group, and the latter group is removed by hydrolysis.
The process of the invention is carried out in an organic solvent or solvent mixture that is indifferent from the point of view of the reactants. For example, aliphatic alcohols such as methyl alcohol, isopropyl alcohol, dialkylamides, preferably dimethylformamide, water or a mixture thereof can be employed. The reaction of the compounds of the formulae II and III is performed either by using an alkali metal salt of the 2-mercaptopyrimidine of the formula II, or in the presence of an acid binding agent. For this purpose, preferably alkali metal carbonates such as sodium or potassium hydrogen carbonate, alkali metal hydroxides such as sodium or potassium hydroxide, alkali earth metal hydroxides such as calcium hydroxide, or tertiary amines such as pyridine, triethylamine or other trialkylamines can be used.
Preferably, the acid binding agent is potassium hydroxide, potassium carbonate or sodium carbonate.
Optionally, the reaction can be accelerated by means of a catalyst. Primarily, alkali metal halides or alkali earth metal halides (for example, potassium iodide, potassium fluoride, sodium bromide or calcium chloride) are used as the catalyst. Preferably, the reaction is carried out in the presence of potassium iodide catalyst.
The reaction is performed at a temperature between room temperature and the boiling point of the reaction mixture, depending on the reactivity of the starting substances. In an aqueous solution it is preferred to proceed at room temperature, in other cases a reaction temperature from 60 to 80° C. is preferred. The reaction time is 2 to 20 hours, depending on the reactivity of the starting substances and the temperature employed.
The starting compounds of the formulae II and III can be used in an equimolar amount or the haloalkylpiperazine of the formula III is added to the reaction mixture in an excess of 10% at the most. The acid binding agent is used in an equimolar quantity, however, it can be employed even in a tenfold excess. When the starting substance is a salt of the mercapto compound, a lower amount of acid binding agent is needed, in general. Calculated for each mole of the 2-mercaptopyrimidine of the formula II, 0.1 to 0.2 moles of the catalyst is used, in general; preferably the reaction is performed in the presence of 0.1 moles of catalyst.
The reaction mixture is worked up in a manner known per se. It is preferred to separate the product as follows: the solution is separated from the precipitated inorganic salts by filtration, the filtrate is evaporated under reduced pressure, and the residue is crystallized from water or an organic solvent, or the precipitated product and inorganic salts are filtered together, and t
Bózsing Dániel
Egyed András
Gacsályi István
Jakóczi Iván
Lévay György
EGIS Gyógyszergyár Rt.
Ford John M.
Heller Ehrman White & MaAuliffe LLP
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